Currently, TBI diagnosis is overly reliant on evaluations of clinical symptoms and advanced brain imaging, a costly, time-consuming approach sometimes complicated by equivocal brain imaging and delayed symptoms. Therefore, efforts are now unfolding to develop biomarkers that not only support the accurate and rapid diagnosis of TBI, but also predict clinical outcomes in patients after head trauma, especially in children with concussions, athletes, military personnel, and first responders.

What laboratory assays for TBI biomarkers have clinical potential?

Mild TBIs rarely cause evident pathology such as hemorrhage or abnormalities that are easily detectable with conventional brain imaging. However, they often induce damage to the blood-brain barrier (BBB), selective swelling, stretching, breakage and disconnection of white matter axons, and neuroinflammation.

Cerebrospinal fluid (CSF):serum albumin ratio is a well-established biomarker of BBB integrity in different neurological conditions. Clinical labs commonly perform CSF analysis, including albumin and total protein measurements. However, in a high percentage of individuals with TBI, BBB remains intact, thus limiting the utility of the CSF:serum albumin ratio as a TBI biomarker. Many clinical labs also evaluate CSF leakage post-head trauma by assessing CSF-specific beta-2 transferrin via immunofixation electrophoresis.

TBIs leading to axonal stretching and mechanical breakage are also associated with CSF release of tau protein. The concentration of this protein in CSF correlates with the severity of the injury, and total tau protein can also be used to monitor recovery in athletes with TBI. However, total tau protein enzyme-linked immunosorbent assays (ELISAs) are only available in some reference laboratories.

Due to its high negative predictive value, studies have shown another marker, S100 protein, to be a useful tool for optimizing clinical decision rules for initial CT scans in patients with TBI and other conditions associated with neuronal damage (e.g. asphyxia, stroke). However, assessment of S100 protein with ELISA is not currently approved for clinical evaluation of patients with head trauma.

Neuron specific enolase (NSE) is found in neuronal and neuroendocrine tissues, and elevated serum NSE levels correlate with poor outcomes in patients with severe trauma and in those who are comatose. Many reference laboratories evaluate NSE in CSF using ELISA or time-resolved amplified cryptate emission immunoassay. However, NSE’s most common application is in the rapid differential diagnosis of dementias (e.g. Creutzfeldt-Jakob disease). Furthermore, NSE is present at high concentrations in erythrocytes. Therefore, the evaluation of this biomarker in CSF and serum samples is limited by contamination with erythrocytes during sample collection and hemolysis, respectively.

What is the better sample: CSF or blood?

Because CSF is in the proximity of the brain, it directly reflects neuronal damage quicker than blood and is not as susceptible to extracerebral influences. However, collecting CSF is more challenging and invasive than a blood specimen. Furthermore, many assays designed for laboratory assessment of TBI biomarkers were developed for serum evaluations, meaning that analysis of these biomarkers in CSF would require additional laboratory validation.

How can researchers advance the use of TBI biomarkers?

TBI researchers previously formed the International Mission for Prognosis and Clinical Trial, or IMPACT, database to study the correlation between patient outcomes and clinical and imaging findings at presentation after head trauma. The healthcare community should now initiate a similar database that includes laboratory data so that biomarkers can be used as another diagnostic factor in the assessment and monitoring of TBI patients.

Alina G. Sofronescu, PhD, NRCC-CC, FACB, is the technical director of the Chemistry Laboratory and assistant professor in the Department of Pathology and Microbiology at University of Nebraska Medical Center in Omaha. +Email: alina.sofronescu@unmc.edu